Bcl-2 controls programmed cell death (apoptosis) pathway on mitochondria and the PI3K/AKT signaling pathway which regulates cell survival from the plasma membrane. Both pathways have been implicated in many cancers and other diseases. While some crosstalk between the two pathways is apparent, much remains to be understood with likely consequences for novel therapeutics for cancer and other diseases. Bcl-2 is characterized by a large, natively unstructured, regulatory loop that serves as a switch for activating its pro- or anti-apoptotic functions on mitochondria as we and others have reported. We recently discovered that the p85a regulatory subunit of phosphoinositide 3-kinase (PI3K) also interacts with the Bcl-2 loop. Our preliminary results demonstrate that the interaction enhances activation of PI3K and its downstream kinase AKT (protein kinase B) in vitro and in vivo and that the activation of PI3K/AKT signaling by Bcl-2 can be dissociated from its anti-apoptotic function. In several cancer cells lines, Bcl-2 expression enhances both basal and growth factor-induced AKT activation. We also found that short peptides derived from the loop of Bcl-2 inhibit Bcl-2/p85a interaction, AKT activation, and cell growth. The central hypothesis we will test is that Bcl-2 interaction with p85a can activate PI3K/AKT signaling by forming an active Bcl-2-containing PI3K signalosome. Our objectives are to use integrated multidisciplinary approaches to address several issues regarding the Bcl-2/p85 interaction: 1). Does Bcl-2 interaction with p85a contribute to elevated PI3K/AKT signaling in cancer cells in vitro and in vivo? 2). How does p85a interact with Bcl-2 and how is the interaction regulated? 3). Can we identify Bcl-2 peptide-based peptidomimetic inhibitors of Bcl-2-mediated PI3K/AKT activation for studying this new Bcl-2-mediated survival pathway? Our proposed studies will unravel a new Bcl-2-mediated PI3K/AKT signal pathway in cancer cells, which likely plays a critical role in enhancing the survival of cancer cells and the development of their resistance to chemo and radiation therapies. Our studies may also result in the identification of leads for developing novel Bcl-2-based PI3K inhibitors for treating human cancer and other lesions where Bcl-2 is often overexpressed.